The following is the summary of “Factors Associated With Developing Neurocognitive Adverse Events in Patients Receiving Lorlatinib After Progression on Other Targeted Therapies” published in the January 2023 issue of Thoracic oncology by Jack, et al.

Lorlatinib’s safety profile features neurocognitive side effects (NAEs). To begin with, the risk factors for NAEs are still not well understood. Potential connections between comorbidities, baseline medicines, and NAEs were investigated by reviewing the medical records of patients who received lorlatinib in prospective investigations at Massachusetts General Hospital (MGH, n=124) and the phase 1/2 B7461001 (NCT01970865; n=248) research.

 The majority of patients (60% at MGH and 49% at B7461001) had a NAE. In the MGH cohort, 40% of patients experienced cognitive impairments, whereas, in the B7461001 cohort, 29% did. The development of cognitive effects in B7461001 was linked to the presence of brain metastases (P=0.008), brain radiation (P=0.033), psychiatric disorder (P=0.008), psychiatric drugs (P<0.001), antiepileptics (P<0.001), and stimulants (P=0.026). Patients in the MGH and B7461001 cohorts experienced adverse mood effects at 36% and 23%, respectively. Brain surgery (P=0.020), psychiatric medications (P<0.001), benzodiazepines (P=0.002), and sedatives (P=0.034) were associated with developing mood effects in B7461001. Psychiatric illness (P=0.02) and stimulants (P=0.01) were also associated with developing mood effects in the MGH cohort. Psychotic symptoms were rare (3% in the MGH cohort and 9% in the B7461001 cohort) but were linked to brain surgery in the MGH group (P=0.001) and age in the B7461001 group (P=0.014). Of the patients in the MGH and B7461001 groups, 23% and 11% experienced speech-related side effects. 

Effects on speech in B7461001 were linked to both brain radiation (P=0.012) and antiepileptic drugs (P<0.001). Only 52% of patients experiencing NAEs in the MGH cohort and 18% in the B7461001 cohort were given dose reductions, both of which had a positive impact.  Lorlatinib frequently causes negative consequences on neurocognition. Multiple conditions, including brain metastases, brain radiation, psychiatric disorder, and neurotropic drugs, may affect lorlatinib-related NAEs.